tbuckley/cabot-search huggingface dataset:
The miR-124-AMPAR pathway connects polygenic risks with behavioral changes shared between schizophrenia and bipolar disorder
Authors: Ho Namkung, Hiroshi Yukitake, Daisuke Fukudome, Brian J. Lee, Mengnan Tian, Gianluca Ursini, Atsushi Saito, Shravika Lam, Suvarnambiga Kannan, Rupali Srivastava, Minae Niwa, Kamal Sharma, Peter Zandi, Hanna Jaaro-Peled, Koko Ishizuka, Nilanjan Chatterjee, Richard L. Huganir, Akira Sawa
Journal: Neuron (2022)
Long noncoding RNA DLGAP1-AS2 promotes tumorigenesis and metastasis by regulating the Trim21/ELOA/LHPP axis in colorectal cancer
Authors: Xue Wang, Han Cheng, Jing Zhao, Jiuming Li, Ying Chen, Kaisa Cui, Lu Tian, Jia Zhang, Chaoqun Li, Shengbai Sun, Yuyang Feng, Surui Yao, Zehua Bian, Shenglin Huang, Bojian Fei, Zhaohui Huang
Journal: Molecular Cancer (2022)

Abstract Background Long noncoding RNAs (lncRNAs) have driven research focused on their effects as oncogenes or tumor suppressors involved in carcinogenesis. However, the functions and mechanisms of most lncRNAs in colorectal cancer (CRC) remain unclear. Methods The expression of DLGAP1-AS2 was assessed by quantitative RT-PCR in multiple CRC cohorts. The impacts of DLGAP1-AS2 on CRC growth and metastasis were evaluated by a series of in vitro and in vivo assays. Furthermore, the underlying mechanism of DLGAP1-AS2 in CRC was revealed by RNA pull down, RNA immunoprecipitation, RNA sequencing, luciferase assays, chromatin immunoprecipitation, and rescue experiments. Results We discovered that DLGAP1-AS2 promoted CRC tumorigenesis and metastasis by physically interacting with Elongin A (ELOA) and inhibiting its protein stability by promoting tripartite motif containing 21 (Trim21)-mediated ubiquitination modification and degradation of ELOA. In particular, we revealed that DLGAP1-AS2 decreases phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) expression by inhibiting ELOA-mediated transcriptional activating of LHPP and thus blocking LHPP-dependent suppression of the AKT signaling pathway. In addition, we also demonstrated that DLGAP1-AS2 was bound and stabilized by cleavage and polyadenylation specificity factor (CPSF2) and cleavage stimulation factor (CSTF3). Conclusions The discovery of DLGAP1-AS2, a promising prognostic biomarker, reveals a new dimension into the molecular pathogenesis of CRC and provides a prospective treatment target for this disease.
metaMIC: reference-free misassembly identification and correction of de novo metagenomic assemblies
Authors: Senying Lai, Shaojun Pan, Chuqing Sun, Luis Pedro Coelho, Wei-Hua Chen, Xing-Ming Zhao
Journal: Genome biology (2022)

Abstract Evaluating the quality of metagenomic assemblies is important for constructing reliable metagenome-assembled genomes and downstream analyses. Here, we present metaMIC ( https://github.com/ZhaoXM-Lab/metaMIC ), a machine learning-based tool for identifying and correcting misassemblies in metagenomic assemblies. Benchmarking results on both simulated and real datasets demonstrate that metaMIC outperforms existing tools when identifying misassembled contigs. Furthermore, metaMIC is able to localize the misassembly breakpoints, and the correction of misassemblies by splitting at misassembly breakpoints can improve downstream scaffolding and binning results.
Author Correction to: T-lymphoid progenitor-based immunotherapies: clinical perspectives for one and all
Authors: P. Gaudeaux, R. D. Moirangthem, J. Paillet, M. Martin-Corredera, H. Sadek, P. Rault, A. Joshi, J. Zuber, T. S. Soheili, O. Negre, I. André
Journal: Cellular and Molecular Immunology (2022)
Selected Articles from This Issue
Journal: Clinical Cancer Research (2022)

PD-1 T tumor-infiltrating lymphocytes (TIL) are a dysfunctional T-cell population characterized by high PD-1 expression and tumor reactivity.To evaluate their potential as a biomarker for durable clinical benefit to PD-1 blockade, Hummelink and colleagues digitally quantified PD-1 T TIL in 120 pretreatment samples from patients with advanced non-small cell lung cancer.PD-1 T TIL showed a high sensitivity in predicting clinical benefit and survival to anti-PD-1 and were superior to PD-L1 or TLS as a biomarker.Importantly, the absence of PD-1 T TIL reliably identified a patient group without benefit from PD-1 blockade, thereby providing a promising tool to reduce overtreatment.
Low intensity near-infrared light promotes bone regeneration via circadian clock protein cryptochrome 1
Authors: Jinfeng Peng, Jiajia Zhao, Qingming Tang, Jinyu Wang, Wencheng Song, Xiaofeng Lu, Xiaofei Huang, Guangjin Chen, Wenhao Zheng, Luoying Zhang, Yunyun Han, Chunze Yan, Qian Wan, Lili Chen
Journal: International Journal of Oral Science (2022)

Abstract Bone regeneration remains a great clinical challenge. Low intensity near-infrared (NIR) light showed strong potential to promote tissue regeneration, offering a promising strategy for bone defect regeneration. However, the effect and underlying mechanism of NIR on bone regeneration remain unclear. We demonstrated that bone regeneration in the rat skull defect model was significantly accelerated with low-intensity NIR stimulation. In vitro studies showed that NIR stimulation could promote the osteoblast differentiation in bone mesenchymal stem cells (BMSCs) and MC3T3-E1 cells, which was associated with increased ubiquitination of the core circadian clock protein Cryptochrome 1 (CRY1) in the nucleus. We found that the reduction of CRY1 induced by NIR light activated the bone morphogenetic protein (BMP) signaling pathways, promoting SMAD1/5/9 phosphorylation and increasing the expression levels of Runx2 and Osterix . NIR light treatment may act through sodium voltage-gated channel Scn4a , which may be a potential responder of NIR light to accelerate bone regeneration. Together, these findings suggest that low-intensity NIR light may promote in situ bone regeneration in a CRY1-dependent manner, providing a novel, efficient and non-invasive strategy to promote bone regeneration for clinical bone defects.
In response to: Defining new reference intervals for serum free light chains in individuals with chronic kidney disease: results of the iStopMM study
Authors: Monique C. Minnema, Joannes F. M. Jacobs
Journal: Blood Cancer Journal (2022)

renal failure, no adjusted reference ranges are installed for the N Latex FLC-ratio [3].However, clinical validation of reference ranges for alternative FLC assays are warranted since international recommendations regarding clinical use of FLC measurements are based on results obtained with the Freelite test [14].We would like to applaud Long et al. and the iStopMM initiative for their incredible important work and hope that with additional analysis the relevance for patients can be further increased.
Surfactant protein D inhibits lipid-laden foamy macrophages and lung inflammation in chronic obstructive pulmonary disease
Authors: Miao-Hsi Hsieh, Pei-Chi Chen, Han-Yin Hsu, Jui-Chang Liu, Yu-Sheng Ho, Yuh Jyh Lin, Chin-Wei Kuo, Wen-Shuo Kuo, Hui-Fang Kao, Shulhn-Der Wang, Zhi-Gang Liu, Lawrence Shih-Hsin Wu, Jiu-Yao Wang
Journal: Cellular and Molecular Immunology (2022)
MEDICC2: whole-genome doubling aware copy-number phylogenies for cancer evolution
Authors: Tom L. Kaufmann, Marina Petkovic, Thomas B. K. Watkins, Emma C. Colliver, Sofya Laskina, Nisha Thapa, Darlan C. Minussi, Nicholas Navin, Charles Swanton, Peter Van Loo, Kerstin Haase, Maxime Tarabichi, Roland F. Schwarz
Journal: Genome biology (2022)

Abstract Aneuploidy, chromosomal instability, somatic copy-number alterations, and whole-genome doubling (WGD) play key roles in cancer evolution and provide information for the complex task of phylogenetic inference. We present MEDICC2, a method for inferring evolutionary trees and WGD using haplotype-specific somatic copy-number alterations from single-cell or bulk data. MEDICC2 eschews simplifications such as the infinite sites assumption, allowing multiple mutations and parallel evolution, and does not treat adjacent loci as independent, allowing overlapping copy-number events. Using simulations and multiple data types from 2780 tumors, we use MEDICC2 to demonstrate accurate inference of phylogenies, clonal and subclonal WGD, and ancestral copy-number states.
DDDR-32. A NEW IMMUNOMODULATORY FUNCTION OF PYRIDO-PYRIMIDINE DERIVATIVES TO IMPAIR METASTATIC GROUP 3 MEDULLOBLASTOMA IN VIVO
Authors: Massimo Zollo, Fatemeh Asadzadeh, Veronica Ferrucci, Pasqualino De Antonellis, Francesca Bibbò, Roberto Siciliano, Carmen Sorice, Giuseppina Criscuolo, Dalim Kardelen Filiz, Melisa Tecik, Stefano Amente, Carmen Daniela Saccà, Francesca Gorini, Emilia Pedone, Donatella Diana, Luciano Pirone, Roberto Fattorusso, Luigi Navas, Vittoria Donofrio, Maria Elena Errico, Pietro Spennato, Lucia De Martino, Lucia Quaglietta, Felice Tirone, Giuseppe Cinalli
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma (MB) is an embryonal tumor of the cerebellum constituting ~ 20% of pediatric brain tumors. To date, four MB molecular groups (further stratified in twelve subtypes) have been described. Among them, Groups 3 and Group 4 MB have the poorest prognosis due to their high metastatic potential. Recently, we have reported a metastatic axis driven by Prune1 overexpression in MB Group3 characterized by canonical TGF-β signaling enhancement and epithelial-mesenchymal transition. Here, we have developed a new not toxic pyrido-pyrimidine derivative with the ability to impair Prune-1-driven-axis, thus ameliorating the survival rate of a murine model of metastatic MB Group3 characterized by overexpression of human Prune1 gene in the cerebellum (under the control of MATH1 promoter). Of importance, this small molecule also is showing immunomodulatory functions thus inhibiting the conversion of tumor-infiltrating T lymphocytes (TILs) to immunosuppressive regulatory T cells (Tregs) in vivo via impairing the secretion of inflammatory cytokines from MB cells. Furthermore, this molecule can also act synergistically with the currently used modified-intensity chemotherapy (e.g. in PNET5 use of Vincristine) or potential in the combination with epigenetics drugs (e.g., LSD1/KDM1A inhibitors). Altogether these results are of importance for future targeted therapies of high-risk metastatic MB. Acknowledgments: We thank for funding support: the Italian Association for Cancer Research (AIRC) Grant IG no. 22129 (M.Z.) and Lazio Innova Grant n. 85-2017-14785 (FT; MZ)
BIOM-35. A NEW PRECISION-MEDICINE APPROACH TO PREDICT TUMOR TREATMENT RESPONSE IDENTIFIES IN GLIOBLASTOMA A 17 GENE SIGNATURE PROGNOSTIC OF TMZ RESPONSE AND SURVIVAL WITH ROBUST PREDICTIVE VALUE
Authors: Mariangela Morelli, Anna Luisa Di Stefano, Alberto Picca, Francesca Lessi, Orazio Santonocito, Michele Menicagli, Francesco Pasqualetti, Sara Franceschi, Paolo Aretini, Marc Sanson, Chiara Maria Mazzanti
Journal: Neuro-Oncology (2022)

Abstract The Glioblastoma (GB) field has been experiencing a therapeutic standstill since 2005, primarily due to ineffective preclinical approaches to test anti-cancer treatments. Therefore, better treatment screening approaches are required. We developed a NADH FLIM-based functional precision medicine approach, that within one week after surgery identified two groups of TMZ Responder and Non-Responder tumors. A 17 gene molecular signature able to classify with 100% precision the TMZ responder and non-responder samples was discovered and identified by Kaplan Meier analysis, a Low-Risk and a High-Risk survival group, interrogating the TCGA GB database (Hazard Ratio = 1.87 p=0.00098,n=148) and TCGA LGG database (Hazard Ratio = 7.66 p=1.197e−35, n=660). Same results were obtained in the CCGA datasets. The 17 gene signature power for independently predicting prognosis (Hazard Ratio = 1.9, p=0.002) was then confirmed by direct RNAseq analysis of a separate clinically characterized cohort of 235 GB patients. Then, we combined the methylation status of the MGMT promoter to analyze the survival status of patients. The survival analysis based on the 17 gene risk signature and MGMT promoter methylation status demonstrated remarkable stratification of the clinical courses into four subgroups. Patients with MGMT promoter unmethylation and 17 gene High-Risk score had the worst prognosis, while patients with MGMT promoter methylation and 17 gene Low-Risk score had the best prognosis. In the latter group, a significant 24-month increase in survival was observed with 10% of 100 months Long Survivors with a difference of 35 months compared to the other groups. Our data indicate a new statistically strong RNAseq-based prognostic survival and TMZ response tool for patients with malignant glioma. The accuracy of this functional precision medicine approach allowed the development of a new prognostic gene signature that can improve the clinical management of GB patients. The approach could be implemented on other cancers as well.
IMMU-27. SIMULTANEOUS TARGETING OF THE PD-L1 AND THE TGF-Β PATHWAYS WITH BINTRAFUSP ALFA IN EXPERIMENTAL GLIOMAS
Authors: Manuela Silginer, Michael Weller, Jenny Kienzler, Nicolas Nunez, Yan Lan, Tobias Weiss, Burkhard Becher, Patrick Roth
Journal: Neuro-Oncology (2022)

Abstract Currently, immunotherapy is one of the most promising research areas in oncology, but immunotherapeutic strategies do not have proven clinical activity against glioblastoma so far. The immunosuppressive microenvironment of gliomas limits an appropriate anti-tumor immune response and represents a major challenge in the context of immunotherapy. Therefore, novel therapeutic strategies that reactivate the immune system and allow for potent anti-glioma immune responses are needed. Bintrafusp alfa is a bifunctional fusion protein that is composed of the extracellular domain of human transforming growth factor-beta receptor type II (TGF-βRII) and a human IgG1 monoclonal antibody blocking programmed death-ligand 1 (PD-L1). It is designed to target the TGF-β and the PDL-1 pathways simultaneously by specifically localizing to the tumor via the anti-PD-L1 moiety and sequestering TGF-β within the tumor microenvironment. We analyzed interrelations between the immunosuppressive factors TGF-β and PD-L1 in glioblastoma samples from patients and observed a significant correlation that points towards a co-regulation of both targets as part of a gene expression network. Next, we assessed the activity of bintrafusp alfa in human and murine glioma cell lines in vitro and observed interference with TGF-β-induced Smad2 phosphorylation as a bona fide response marker of TGF-β pathway activation and an increase in immune cell-mediated glioma cell killing. In vivo, bintrafusp alfa prolonged the survival of glioma-bearing immunocompetent mice, whereas the survival benefit was absent in immunodeficient Rag1-/- mice lacking T and B cell populations. Characterization of the tumor microenvironment by immunohistochemistry and high-dimensional flow cytometry confirmed the immune-activating effects of bintrafusp alfa. In summary, these encouraging results demonstrate that novel treatment options such as bintrafusp alfa may have the potential to overcome the lack of immunogenicity and reinvigorate anti-tumor immune responses to efficiently combat glioblastoma.
IMMU-14. MENINGEAL PLASMA CELLS MOUNT AN IMMUNOLOGICAL DEFENSE AGAINST GLIOBLASTOMA
Authors: Leo Ampie, Dorian McGavern
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Glioblastoma (GBM) represents the deadliest primary intracranial neoplasm. While many studies have focused on T cell responses to GBM, few have examined the role of humoral immunity. Here, we sought mechanistic insights into the anatomy and function of the humoral response against GBM. METHODS: C57BL/6J mice were injected stereotactically with syngeneic SB28 tumor cells. Humoral immunity was evaluated in the spleen and blood by high parameter flow cytometry and the meninges, brain, and spleen by confocal microscopy. The function importance of humoral immunity was interrogated using CD4-/- and IgA-/- mice and via transcranial application of the plasma cell survival factor, APRIL. RESULTS: High parameter flow cytometry revealed a significant increase of plasma B cells (CD19+, CD138+) in the spleen and blood of GBM mice within two weeks. Using blimp-1 reporter mice, we observed that IgA+ plasma cells localized to extrafollicular splenic regions and along meningeal dural venous sinuses near newly generated blood and lymphatic vessels that connected directly to the tumor. Decreased survival was observed in IgA-/- but not CD4-/- mice injected with SB28 cells, suggesting that a T helper independent IgA response plays a role in controlling GBM. This response was enhanced therapeutically by transcranial application of APRIL. CONCLUSION: Our results demonstrate that GBM elicits a systemic and meningeal humoral response, which plays in limiting GBM growth and can be transcranially enhanced via APRIL. The participation of IgA+ plasma cells in GBM immunity offers new possibilities for therapeutic intervention in this deadly disease.
EOLP-01. PALLIATIVE CARE REFERRAL ACROSS THE DISEASE TRAJECTORY IN HIGH-GRADE GLIOMA
Authors: Rita Crooms, Jennie Taylor, Nathalie Jette, Rachelle Morgenstern, Parul Agarwal, Nathan Goldstein, Barbara Vickrey
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Patients with high-grade glioma (HGG), WHO grade 3 or 4, have substantial palliative care needs. As evidence suggests early palliative care consultation (PCC) yields improved quality of life in advanced cancer, our aim was to determine the occurrence, timing, and factors associated with PCC in HGG. METHODS Adults with HGG diagnosed between 8/3/2011 and 1/23/2020 were identified retrospectively from a large, academic, multi-center health system cancer registry. Patients were stratified by any prior PCC (yes/no), and timing of PCC by disease phase: (1) diagnosis (before radiation), (2) initial treatment (first-line chemotherapy/radiation), (3) second-line treatment (second-line to last chemotherapy), and (4) end-of-life (after last chemotherapy). Univariate analyses (e.g., Chi-square test) were conducted to compare PCC to non-PCC groups, based on data distribution. RESULTS Of 621 HGG patients, 134 (21.58%) received PCC, with 14 (10.45%) referred during phase 1; 35 (26.12%) in phase 2; 20 (14.93%) in phase 3; and 65 (48.51%) in phase 4 with a median of 74 days (IQR 15, 277) from initial PCC to death. The majority of referrals were inpatient (111 (82.84%)). The PCC group did not differ significantly from non-PCC in age, sex, language, race, or ethnicity, but did differ by marital status: single (263 (42.35%) vs 187 (38.4%)), divorced/separated (37 (27.61%) vs 107 (21.97%)), married/civil union (17 (12.69%) vs 154 (31.62%)); (Chi-square p &amp;lt; .01). Compared to non-PCC, more patients in the PCC group had glioblastoma histopathology (89.55% vs. 82.14%, p = .04). CONCLUSION A minority of HGG patients ever received PCC, which primarily occurred in the inpatient setting, and half of those referred for PCC received it during the end-of-life phase. Thus, only about one in 10 patients in the entire cohort potentially received the benefits of early PCC. Further studies should elucidate barriers and facilitators to early palliative care in HGG.
EPCO-09. TRANSCRIPTOMIC LANDSCAPE OF LOWER GRADE GLIOMA BASED ON AGE-RELATED NON-SILENT SOMATIC MUTATIONS
Authors: Kyoung Su Sung, Jaejoon Lim
Journal: Neuro-Oncology (2022)

Abstract Glioma accounts for 80% of all malignant brain tumours and is the most common adult primary brain tumour. Age is an important factor affecting the development of cancer, as somatic mutations accumulate with age. Here, we aimed to analyse the significance of age-dependent non-silent somatic mutations in glioma prognosis. Histological tumour grade depends on age at diagnosis in patients with IDH1, TP53, ATRX, and EGFR mutations. Age of patients with wild-type IDH1 and EGFR increased with increase in tumour grade, while the age of patients with IDH1 or EGFR mutation remained constant. However, the age of patients with EGFR mutation was higher than that of patients with IDH1 mutation. The hierarchical clustering of patients was dominantly separated by IDH1 and EGFR mutations. Furthermore, patients with IDH1 mutation were dominantly separated by TP53 and ATRX double mutation and its double wild-type counterpart. The age of patients with ATRX and TP53 mutation was lower than that of patients with wild-type ATRX and TP53. Patients with the double mutation showed poorer prognosis than those with the double wild type genotype. Unlike IDH1 mutant, IDH1 wild-type showed upregulation of expression of epithelial mesenchymal transition associated genes.
EPCO-12. SEX-SPECIFIC PATTERNS CONNECTING LOCOREGIONAL MRI FEATURES AND IMMUNOHISTOCHEMISTRY OF IMAGE-LOCALIZED BIOPSIES OF GLIOBLASTOMA
Authors: Jazlynn Langworthy, Pamela Jackson, Andrea Hawkins-Daarud, Sara Ranjbar, Kyle Singleton, Deborah Boyett, Michael Argenziano, Jack Grinband, Peter Canoll, Kristin Swanson
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor with a median survival of 14 months. GBMs are challenging to treat due to their heterogeneous nature. It has also been seen that these tumors have sex differences in their cellular subtypes as well as imaging. Radiomics has the potential to provide a non-invasive, spatial understanding of genetic and epigenetic diversity in these complex tumors and to aid in treatment planning. We have an ongoing study to obtain image-localized biopsies from GBM patients, allowing us to complete radiomic analysis and make connections between immunohistochemistry (IHC) and magnetic resonance imaging (MRI) features. We sought to determine if the patterns on imaging were correlated with underlying tumor biology. We focused on immunohistochemistry (IHC) markers of key features of tumor biology including SOX2 for stem-like tumor cells, CD68 for immune response and Ki67 for proliferation kinetics. Our study included 38 patients with a total of 99 biopsies (bxs): 27 males with 77 bxs and 11 females with 22 bxs. Biopsies were sectioned and stained for the SOX2, CD68, and KI67 markers. We computed 18 first-order radiomic features at each biopsy location for patients’ multimodal MRIs: T1W, T1Gd, T2W, FLAIR, apparent diffusion coefficient, diffusion weighted imaging (DWI) and susceptibility weighted imaging. We then performed correlation analysis between each radiomic feature and marker abundance for each IHC stain. Overall, we found sex-distinct patterns connecting imaging with these IHC markers. For example, amongst female patients, DWI held more prominent correlations with SOX2 than in males. Whereas there were more correlations between CD68 IHC abundance and T1Gd imaging features in males compared to females. Taken together, the overall patterns connecting locoregional imaging features to these IHC markers showed sex-distinct patterns suggesting the potential for sex to be an important biological variable when interpreting the biology underlying imaging changes.